US3784551A - 2-oxo-1,4-dioxa-8-azaspiro (4.5) decanes and related compounds - Google Patents
2-oxo-1,4-dioxa-8-azaspiro (4.5) decanes and related compounds Download PDFInfo
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- US3784551A US3784551A US00160937A US3784551DA US3784551A US 3784551 A US3784551 A US 3784551A US 00160937 A US00160937 A US 00160937A US 3784551D A US3784551D A US 3784551DA US 3784551 A US3784551 A US 3784551A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/10—Spiro-condensed systems
Definitions
- each of R and R is H, CH C H phenyl pchlorophenyl or benzyl;
- X is O or S;
- R is H and R is H, alkyl of 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, butyl), methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, benzyl, phenethyl, pyridylmethyl (e.g.
- the compounds of Formula I wherein R is C alkyl are produced by alkylating a compound of Formula V with formaldehyde (for methylation) or dialkyl sulfate such as dimethyl sulfate, diethyl sulfate or dibutyl sulfate.
- the methylation with formaldehyde is carried out by heating the mixture of a compound of Formula V and formaldehyde and, if desired in the presence of formic acid, under reflux for l to hours.
- the alkylation with dialkyl sulfate is carried out in a solvent such as ether (e.g. ethyl ether, propyl ether, butyl ether), chloroform or benzene, in the presence of a deacidifying agent such as alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide or alkali metal alkoxide for several to hours.
- a solvent such as ether (e.g. ethyl ether, propyl ether, butyl ether), chloroform or benzene
- a deacidifying agent such as alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide or alkali metal alkoxide for several to hours.
- the benzyl elimination is carried out by subjecting a compound (VII) (R being benzyl) to catalytic reduction using a catalyst such as palladium-carbon, palladium 0xide or Raney-nickel, in an inert solvent such as water, methanol, ethanol, 2-propanol, glacial acetic acid or dioxane under normal or increased pressure at room temperature up to about 100 C. for 1 to 20 hours.
- a catalyst such as palladium-carbon, palladium 0xide or Raney-nickel
- the alkoxycarbonyl elimination is carried out by treating a compound (VII) (R being C alkoxycarbonyl) with an acid such as hydrogen chloride, hydrogen bromide, hydrogen fluoride or perchloric acid in a solvent, preferably with 10-25 hydrogen bromide in acetic acid, under anhydrous conditions to avoid the decomposition of the spiro ring, or with an alkali such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide or magnesium hydroxide in a solvent such as water, methanol, ethanol, 2-propanol, ethylene glycol or trimethylene glycol at about boiling point of the solvent employed for 2 to 25 hours.
- an acid such as hydrogen chloride, hydrogen bromide, hydrogen fluoride or perchloric acid
- a solvent preferably with 10-25 hydrogen bromide in acetic acid
- an alkali such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide or magnesium hydroxide in a solvent such
- the compounds of Formula I can be converted into acid addition salts with various inorganic acids (e.g. hydrochloric, hydrobromic, nitric, sulfuric acid) or various organic acids (e.g. oxalic, maleic, fumaric, tartaric acid), and also into quaternary ammonium salts with methyl chloride, methyl bromide, methyl iodide, butyl iodide methyl hydrogensulfate or dimethyl sulfate.
- various inorganic acids e.g. hydrochloric, hydrobromic, nitric, sulfuric acid
- organic acids e.g. oxalic, maleic, fumaric, tartaric acid
- the compounds of Formula I as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts have acetylcholine antagonistic activity and gastric juice secretion inhibiting activity, and are useful as drugs for the treatment of various gastro-enteric spasms (algospasms), gastric hyperacidities and gastro-enteric ulcers.
- Acetylcholine antagonistic activity was tested according to the method described by J. M. Van Rossum et al. in Archives Internatationales de Pharmacodynamie et de Therapie, vol. 143, pages 240246 and 299-330 (1963).
- pA is the negative of the logarithm, to the base 10, of the molar concentration of the test compound which reduced the eifect of twice dose of acetylcholine on contracting action of the guinea pig intestine to that of a single dose.
- Acetylcholine antagonistic Test compound activity, pA 3 N Atropine (for comparison) 9.2 Scopolamine-N-butyl bromide (for comparison) 7.1
- Compound I 1 Sodium chloride 9 Water for injection; a suflicient amount to make 1 ml.
- compositions may be administered orally or parenterally, usual daily doses lying in the range of 1.5 to 6.0 mg. per human adult.
- g., ml., M.P. and B.-P. represent gram(s), milliliter(s), melting point and boiling point, respectively.
- EXAMPLE 1 A mixture of 17.1 g. of l-ethoxycarbonyl-4-oxopiperidine, 11 g. of thioglycolie acid and 0.3 g. of p-toluenesulfonic acid in 200 ml. of benzene is heated under reflux 6 hours. After cooling, the reaction mixture is washed with water, with sodium bicarbonate solution and again with water. The mixture is dried over anhydrous sodium sulfate, and the residue is distilled 01f under reduced pressure. The residue is distilled under vacuum to give 17 g.
- EXAMPLE 2 A mixture of 18.9 g. of 1-benzyl-4oxopiperidine, 15.2 g. of DL-mandelic acid and 8 m1. of concentrated sulfuric acid in 400 ml. of chloroform is heated under reflux with stirring in a flask with a water trap attached for 9 hours. After cooling, a viscous oil layer separates. The viscous oil is collected by decantation, and alkalified with an aqueous potassium carbonate solution. The crystals that formed are collected by filtration, washed with water and recrystallized from 2-propanol to give 20 g. of 8- benzyl-2-oxo-3-phenyl-1,4-dioxa 8 azaspiro [4.5]decane as white crystals melting at 127 C. Its hydrochloride melts at 226 C.
- CH CHC O- 32 CH; 2 .-.-do...-:..-; ..d0 -.r-
- EXAMPLE 52 A mixture of 9.6 g. of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (3-quinuclidin0ne hydrochloride), 7.5 g. of
- the chloand the filtrate is concentrated under reduced pressure. 50 rofo 1ayer i Washed i h water d dried over anhy. The residue is extracted with chloroform, the chloroform drous magnesium sulfate, and then the chloroform is layer is washed three times with water and dried over di ill d ff t give 11 g. of 3,3-diphenyl-2-oxo-1,4-dioxaanhydrous magnesium Sulfate, and then the chloroform 8-azaspiro[4.5]decane as white crystals melting at 113 is distilled off.
- EXAMPLE 65 To a solution of 8 g. of 8-methyl-3,3-diphenyl-2-oxo-1, 4-dioxa-8-azaspiro[4.5]decane (produced by Example 32) in a mixed solvent of 80 ml. of chloroform plus 30 ml. of methanol is added 5 g. of methyl iodide. The mixture is heated under reflux with stirring for 2.5 hours, and then further heated for 2.5 hours to complete the reaction. After cooling, the crystals obtained are collected by filtration and recrystallized from methanol to give 8 g. of 8,8 dimethyl-3,3-diphenyl-2-oxo-l,4-dioxa-8-azaspiro [4.5]decanium iodide as white crystals melting at 266- 267 C. (decomposition).
- R and R are members selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a p-chlorophenyl group and a benzyl group;
- X is a member selected from the group consisting of an oxygen atom and a sulfur atom;
- R represents a hydrogen atom;
- R is a member selected from the group consisting of a hydrogen atom, an alkyl group of from 1 to 4 carbon atoms, a methoxy-carbonyl group, an ethoxy carbonyl group, an acetyl group, a benzoyl group, a benzyl group, a phenethyl group, a pyridylethyl group, a furfuryl group, a thenyl group, an allyl group and a propargyl group; and
- a compound according to claim 1 said compound being 8 (2 thenyl) 3,3-diphenyl-2-oxo-1,4-dioxa-8- azaspiro [4.5 decane.
- a compound according to claim 1 said compound being 8 methyl 3,3 diphenyl 2 oxo-1,4-dioxa-8- azaspiro [4.5 decane methyl hydrogensulfate.
- a compound according to claim 1 said compound being 8 methyl 3,3 diphenyl 2 oxo-1,4-dioxa-8- azaspiro[4.5]decane dimethyl sulfate.
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Abstract
SPIRO COMPOUNDS OF THE FORMULA
(-CH(-R3)-(CH2)M-N(-R4)-(CH2)N-)>C<(-X-C(-R1)(-R2)-COO-)
WHEREIN EACH OF R1 AND R2 IS H, CH3 C2H5, PHENYL, PCHLOROPHENYL OR BENZYL; X IS O OR S; R3 IS H AND R4 IS H, ALKYL OF 1 TO 4 CARBON ATOMS, METHOXYCARBONYL, ETHOXYCARBONYL, ACETYL BENZOLYL, BENZYL, PHENETHYL, PYRIDYLMETHYL, PYRIDYLETHYL, FURFURYL, THENYL, CINNAMYL, CINNAMOYL, ALLYL OR PROPARGYL, AND M PLUS N IS 2 OR 3 (M BEING 0 OR 1 AND N BEING 2 OR 3); OR R3 AND R4 COMBINEDLY REPRESENT :CH2-CH3-, M IS 2 AND N IS 1, AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION AND QUATERNARY AMNONIUM SALTS THEREOF ARE USEFUL AS ACETYLCHLORINE ANTAGONISTIC AGENTS AND GASTRIC JUICE SECRETION INHIBITING AGENTS.
(-CH(-R3)-(CH2)M-N(-R4)-(CH2)N-)>C<(-X-C(-R1)(-R2)-COO-)
WHEREIN EACH OF R1 AND R2 IS H, CH3 C2H5, PHENYL, PCHLOROPHENYL OR BENZYL; X IS O OR S; R3 IS H AND R4 IS H, ALKYL OF 1 TO 4 CARBON ATOMS, METHOXYCARBONYL, ETHOXYCARBONYL, ACETYL BENZOLYL, BENZYL, PHENETHYL, PYRIDYLMETHYL, PYRIDYLETHYL, FURFURYL, THENYL, CINNAMYL, CINNAMOYL, ALLYL OR PROPARGYL, AND M PLUS N IS 2 OR 3 (M BEING 0 OR 1 AND N BEING 2 OR 3); OR R3 AND R4 COMBINEDLY REPRESENT :CH2-CH3-, M IS 2 AND N IS 1, AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION AND QUATERNARY AMNONIUM SALTS THEREOF ARE USEFUL AS ACETYLCHLORINE ANTAGONISTIC AGENTS AND GASTRIC JUICE SECRETION INHIBITING AGENTS.
Description
United States Patent 3,784,551 2-0X0-1,4-Dll0XA-8-AZASPIRO (4.5) DECANES AND RELATED COMPOUNDS Michio Nakanishi, Oita, Katsuo Arimura, Yoshitomi, and
Hideki A0, Oita, Japan, assignors to Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan No Drawing. Filed July 8, 1971, Ser. No. 160,937 Int. Cl. C07d 99/04, 99/06 US. Cl. 260-293. 11 Claims ABSTRACT OF THE DISCLOSURE Spiro compounds of the formula 33 CHn H XC(R1)(R2) M wherein each of R and R is H, CH C H phenyl, pchlorophenyl or benzyl; X is O or S; R is H and R is H, alkyl of 1 to 4 carbon atoms, methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, benzyl, phenethyl, pyridylmethyl, pyridylethyl, furfuryl, thenyl, cinnamyl, cinnamoyl, allyl or propargyl, and m plus n is 2 or 3 (m being 0 or 1 and n being 2 or 3); or R and R combinedly represent CH -CH m is 2 and n is 1, and pharmaceutically acceptable acid addition and quaternary ammonium salts thereof are useful as acetylchlorine antagonistic agents and gastric juice secretion inhibiting agents.
PRIOR ART 1) In our copending application, filed Dec. 31, 1970, Ser. No. 103,322, now US. 3,723,442, there are disclosed spiro piperidine compounds of the formula la ll and pharmaceutically acceptable acid addition salts there of, wherein R is H, acetyl, allyl, 2-propynyl, 2-cyanoethyl, C alkyl, C alkoxy carbonyl, C alkoxycarbonylethyl, benzoyl, benzyl or phenethyl, each of R and R is H, methyl, ethyl or phenyl, R is H, C alkyl, benzyl, phenyl or substituted phenyl, the substituent being selected from the group consisting of Cl, CH CH O or CF;,, and n is 0 or 1, which have strong reserpine antagonistic activity and blood sugar lowering action.
(2) British Pat. No. 1,203,430 discloses heterocyclic spiro compounds of the formula and pharmaceutically acceptable acid addition salts thereof, wherein R is hydrogen, an alkyl group of 1 to 4 carbon atoms, lower alkenyl, lower alkynyl, lower alkoxycarbonyl, benzyloxycarbonyl, lower alkoxy-lower alkyl, phenoxy-lower alkyl, benzoyl, trimethoxybenzoyl or aralkyl optionally substituted by halogen, nitro or lower alkyl, R is hydrogen or lower alkyl, R is hydrogen, lower alkyl, cycloalkyl, aralkyl oraryl optionally substituted by halogen, lower alkyl, lower akoxy or trifluoromethyl, and n is 0 or 1 where the term lower means that the alkenyl, alkynyl, alkoxycarbonyl, alkyl or alkoxy has not more that four carbon atoms, which are useful as psychotropic drugs.
This invention relates to novel and therapeutically valuable spiro compounds of the formula as well as pharmaceutically acceptable acid addition and quaternary ammonium salts thereof. In the above formula, each of R and R is H, CH C H phenyl pchlorophenyl or benzyl; X is O or S; R is H and R is H, alkyl of 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, butyl), methoxycarbonyl, ethoxycarbonyl, acetyl, benzoyl, benzyl, phenethyl, pyridylmethyl (e.g. 2-pyridylmethyl, 3-pyridihnet-hyl), pyridylethyl (e.g. 2-pyridylethyl, 4-pridylethyl), furfuryl, thenyl (Z-thenyl, 3-thenyl), cinnamyl, cinnamoyl, allyl or propargyl, and m is plus n is 2 or 3 (m being 0 or 1 and n being 2 or 3); or, R and R combinedly represent -CH CH m is 2 and n is 1. In this latter case the compounds of Formula I are quinuclidine spiro compounds which can be represented by the formula The compounds of Formula I can be produced by the following methods:
(i) By the reaction of a compound of the formula wherein A is CO- or -C(OH)a-, with a compound of the formula R1. H-X-d-GOOH 1'1 (IV) This reaction is usually carried out (a) in a solvent such as benzene, toluene, xylene, chloroform, dichloroethane, carbon tetrachloride, methanol, ethanol, Z-propanol or dioxane, in the presence of an acid catalyst such as ptoluenesulfonic, benzenesulfonic, sulfuric, phosphoric or hydrochloric acid, under reflux for 5 to 20 hours, while water produced is removed from the reaction system, or (b) in a solvent such as methanol, ethanol, 2-propan0l, dioxane, chloroform, tetrahydrofuran, benzene, toluene or xylene, in the presence of a dehydrating agent such as calcium oxide, anhydrous magnesium sulfate, anhydrous zinc chloride, molecular sieve or N,N'-dicyclohexylcarbodiimide, at room temperature or an elevated temperature, for example at the boiling point of a solvent employed, for 3 to 20 hours. 7
(ii) By the reaction of the compound of the formula )CHzhCI-In X-C (R (R2) CH9, 0- =0 (V) with a compound of the formula R Y (VI) alkali metal hydrogen carbonate, alkali metal hydroxide, alkali metal alkoxide, trimethylamine, triethylamine, N,N- diethylaniline or pyridine, under reflux for 3 to 20 hours.
(iii) The compounds of Formula I wherein R is C alkyl are produced by alkylating a compound of Formula V with formaldehyde (for methylation) or dialkyl sulfate such as dimethyl sulfate, diethyl sulfate or dibutyl sulfate.
The methylation with formaldehyde is carried out by heating the mixture of a compound of Formula V and formaldehyde and, if desired in the presence of formic acid, under reflux for l to hours.
The alkylation with dialkyl sulfate is carried out in a solvent such as ether (e.g. ethyl ether, propyl ether, butyl ether), chloroform or benzene, in the presence of a deacidifying agent such as alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide or alkali metal alkoxide for several to hours.
(iv) The compounds of Formula I wherein R is hydrogen atom are produced by eliminating R" group in a compound of the formula CH2)n O =0 (VII) wherein R" is benzyl or C alkoxycarbonyl.
The benzyl elimination is carried out by subjecting a compound (VII) (R being benzyl) to catalytic reduction using a catalyst such as palladium-carbon, palladium 0xide or Raney-nickel, in an inert solvent such as water, methanol, ethanol, 2-propanol, glacial acetic acid or dioxane under normal or increased pressure at room temperature up to about 100 C. for 1 to 20 hours.
The alkoxycarbonyl elimination is carried out by treating a compound (VII) (R being C alkoxycarbonyl) with an acid such as hydrogen chloride, hydrogen bromide, hydrogen fluoride or perchloric acid in a solvent, preferably with 10-25 hydrogen bromide in acetic acid, under anhydrous conditions to avoid the decomposition of the spiro ring, or with an alkali such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide or magnesium hydroxide in a solvent such as water, methanol, ethanol, 2-propanol, ethylene glycol or trimethylene glycol at about boiling point of the solvent employed for 2 to 25 hours.
The compounds of Formula I can be converted into acid addition salts with various inorganic acids (e.g. hydrochloric, hydrobromic, nitric, sulfuric acid) or various organic acids (e.g. oxalic, maleic, fumaric, tartaric acid), and also into quaternary ammonium salts with methyl chloride, methyl bromide, methyl iodide, butyl iodide methyl hydrogensulfate or dimethyl sulfate.
The compounds of Formula I as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts have acetylcholine antagonistic activity and gastric juice secretion inhibiting activity, and are useful as drugs for the treatment of various gastro-enteric spasms (algospasms), gastric hyperacidities and gastro-enteric ulcers.
For example, the compounds of Formula I listed below (A, B, N) have the following pharmacological properties.
(A) 8 methyl-3,3-diphenyl-2-oxo-1,4-dioxa-8 azaspiro [4.5]decane methoiodide (B) 8 butyl-3,3-diphenyl-2-oxo-1,4-dioxa 8 azaspiro [4.5]decane methoiodide (C) 8 methyl-3-methyl-3-phenyl-2-oxo-1,4-dioxa-8-azaspiro[4.5]decane methoiodide (D) 8 methyl-3-benzy1-3-phenyl-2-oxo-1,4-dioxa-8-azaspiro[4.5]decance methoiodide (E) 8 (2 thenyl)-3,3-diphenyl-2-oxo-1,4-dioxa-8-azaspiro [4.5 decane methoiodide (F) 8 methyl 3,3-diphenyl 2 oxo-1-oxa-4-thia-8-azaspiro [4.5]decane hydrochloride 4 (G) 8 methyl 3,3-diphenyl-2-oxo-1-oxa-4-thia-8-azaspiro [4.5]decane methoiodide (l-l) 8-rnethyl-3,3-diphenyl-2-oxo-1,4 dioxa 8-azaspiro [4.5 decane ethobromide (J) 8 methyl-3,3-diphenyl-2 oxo-1,4-dioxa-8 azaspiro [4.5]decane methyl hydrogensulfate (K) 8 methyl-3,3-diphenyl-2-oxo-1,4-dioxa-8 azaspiro [4.5]decane dimethyl sulfate (L) 8 cinnamyl 3,3-diphenyl-2-oxo-1,4-dioxa 8-azaspiro[4.5 1 decane methoiodide (M) 1 azabicyclo[2.2.2]octane-3 spiro-2' (5',5'-diphenyl-l',3'-dioxolan-4'-one) methoiodide (N) 1 azabicyclo[2.2.2]octane-3 spiro 2' (5',5'-dipheny1-1',3 '-dioxolan-4-one) maleate The tests were carried out by the following procedures:
(A) Acetylcholine antagonistic activity Acetylcholine antagonistic activity was tested according to the method described by J. M. Van Rossum et al. in Archives Internatationales de Pharmacodynamie et de Therapie, vol. 143, pages 240246 and 299-330 (1963). pA is the negative of the logarithm, to the base 10, of the molar concentration of the test compound which reduced the eifect of twice dose of acetylcholine on contracting action of the guinea pig intestine to that of a single dose.
The results are shown in Table 1.
TABLE 1 Acetylcholine antagonistic Test compound: activity, pA 3 N Atropine (for comparison) 9.2 Scopolamine-N-butyl bromide (for comparison) 7.1
(B) Eflect on gastric juice secretion in Shay rats Effect on gastric juice secretion was tested according to the method described by Paul Bass and Margaret A. Patterson in The Journal of Pharmacology and Experimental Therapeutics, vol. 156, pages 142-149 (1967). Wistar strain female rats (-200 g.) were deprived of meal for 48 hours and the pylorus was ligated. ED shows the subcutaneous dose of the test compound required for 50% depression of gastric juice secretion against the control Shay rats.
The results are shown in Table 2.
TABLE 2 Depressive effect on gastric uice secretion in Shay rats,
Test compound: ED (mg./ kg.)
Compound I 1 Sodium chloride 9 Water for injection; a suflicient amount to make 1 ml.
(2) 0.5 mg. tablets are prepared from the following composition:
Compound I 0.5 Lactose and starch 70.5 Microcrystalline cellulose 5.0 Methyl cellulose 1.0 Magnesium stearate 1.0 Talc 2.0
Total (per tablet) 80.0
The pharmaceutical compositions may be administered orally or parenterally, usual daily doses lying in the range of 1.5 to 6.0 mg. per human adult.
In the following examples, g., ml., M.P. and B.-P. represent gram(s), milliliter(s), melting point and boiling point, respectively.
EXAMPLE 1 A mixture of 17.1 g. of l-ethoxycarbonyl-4-oxopiperidine, 11 g. of thioglycolie acid and 0.3 g. of p-toluenesulfonic acid in 200 ml. of benzene is heated under reflux 6 hours. After cooling, the reaction mixture is washed with water, with sodium bicarbonate solution and again with water. The mixture is dried over anhydrous sodium sulfate, and the residue is distilled 01f under reduced pressure. The residue is distilled under vacuum to give 17 g. of S-ethoxycarbonyl-Z-oxo 1 oxa 4 thia-8-azaspiro- [4.5]decane as pale yellow liquid boiling at l77-l79 C./0.2 mm. Hg and showing n =l.520. The liquid product solidifies on standing. The solid melts at 42- 45 C.
EXAMPLE 2 A mixture of 18.9 g. of 1-benzyl-4oxopiperidine, 15.2 g. of DL-mandelic acid and 8 m1. of concentrated sulfuric acid in 400 ml. of chloroform is heated under reflux with stirring in a flask with a water trap attached for 9 hours. After cooling, a viscous oil layer separates. The viscous oil is collected by decantation, and alkalified with an aqueous potassium carbonate solution. The crystals that formed are collected by filtration, washed with water and recrystallized from 2-propanol to give 20 g. of 8- benzyl-2-oxo-3-phenyl-1,4-dioxa 8 azaspiro [4.5]decane as white crystals melting at 127 C. Its hydrochloride melts at 226 C.
EXAMPLE 3 A mixture of 4.7 g. of 4,4-dihydroxypiperidine hydrochloride, 4.7 g. of Z-mercaptopropionic acid and 2 to 3 drops of concentrated sulfuric acid in ml. of chloroform is heated under reflux in a flask with a water trap attached for 8 hours. After cooling, the crystals formed are collected by filtration and recrystallized from methanol to give 2.3 g. of 3-methyl 2 oxo-l-oxa-4-thia-8- azaspiro [4.5]decane hydrochloride as white crystals melting at 228 C.
EXAMPLES 4 TO 51 Other examples of compounds (I) (R being H) and acid addition salts thereof which can be produced from a compound (III) (R being H) and a compound (IV) in a manner similar to that described in Examples 1 to 3 with stirring in a flask provided with a water trap for 8 40 are as follows:
Example R m n X R R Physical constant 4-- FT 1 2 O H CHs--..; HC1M.P.:229 C.
5... FT 1 2 S H.... H HE! M.P.: 212213 C.
6..-..-.-.---. H 1 2 S H ".2 HBr M.P.: 245 C. (decomposition).
7.. H 1 2 O Same as above M.P.:113 0., HBr M.P.: 241 C.
8- H 1 2 O C2H5- d0 Oxalate M.P.: 205 C.
10 H.--.'. 1 2 0 CH3- CHz- HBI'M.P.Z184=185 C.
11. FT 1 2 0 CH G Acid maleate M.P.: 175 C.
12.. H 1 2 o H.-'.--..'.-.*.-.-.-:.-; H H01 MR: 212 C. (decomposition).
13. H 1 2 O H---.; Q HC1M.P.: 194-195 C. (decomposition).
15 C2H5OC0-.....; 1 2 O H H M.P.2 61-63" 0., B.P.: -148 C./0.2 mm. Hg,
17.......... C2H5OCO....
2 0 H Same as above M.P.: 80 C.
18. CzHsO G O- 1 2 S CH:---.. CH;- B.P.: 1454491015 mm. Hg, 'nn =1.5028.
19 CzH5OCO--- 1 2 0 03H: Q flD =1.5137.
20......'..;.- C2HsOCO-- 1 2 0 G Sameasabove...... M.P.:96 C.
22 CzH5OCO-..... 0 2 S H H B.P.: 148-150 C./0.2 mm. Hg. 7LD -=1.5190.
TABLEContinued Example R n R IR Physical constant 23 CzH OCO- 2 CH:..-.;-.--.'.' Q B.P.:180183 C./0.25m1n. Hg,'nr) =1.5169.
24 2 H H Maleate M.P.:182 C.
25.. Same as above -.t 2 H CHz- HC1M.P.:250 C.
76 (7n 2 HCI M.P.: 236-237 C.
3 Same as above Same as above M.P.: 107 0., oxalate M.P.: 178-179 C. 2 H H H01 M.P.: 168 0., male-ate M.P.: 154-155 (3,,
29 2 M.P.: 135 0., maleate M.P.: 180 C.
CH2CH2 30 2 Same as above.. Same as above. M.P.: 81 C.
CH=CHCH2- 31 2 -.-.-d0 --d0 M.P.:134-135 O.
CH=CHC O- 32 CH; 2 .-.-do...-:..-; ..d0 -.r-
E3? 0., H01 M.P.: 254 0., oxalate M.P.:
33-. CH3- 2 H. -..c 01 G M.P.: 82-84" C., HC1M.P.: 222223 C.
34 CHa- L 2 H M.P.: 54 0., H01 M.P.: 207208 0., maleate M.P.: 148-149 C.
35 CHa 1'. 2 CH:...--. CHz- HCI M.P.: 228 C., 71 =L548L '16 CH;- 2 H CH3- HClM.P.:261 C. (decomposition),nu =1.4668.
37 0113- 2 CH;- HC1M.P.: 232 C.
38 CHz- 2 Q Same as above M.P.: 92-94 0., H01 M.P.: 221 C 39 CH; 2 Same as above.- Oxalate M.P.: 174-175 C.
40 CgH5- 2 do M.P.:106" C.
41 CH3(CHZ)3 2 -.-..d0 Same as above M.P.: 0., malcate M.P.:150-151" C.
0113-c0- 2 ..do d M.P.: ss-s9 c.
43 2 H CHa- M.P.:112-113 C.
44 Same as above 2 M.P.: 127 C.
45 S 2 0H.- cm- MaleateM.P.:175 0.
46 Same as above 2 Maleate M.P.: 198 C. (decomposition).
41 CH 2 Same as above... Same as above Maleate M.P.:175 C. (decomposition).
48 2 0 .-'-'-.d0 in-do M.P.: 104 0., 2HC1 M.P.: 232 C. (decomposi- CHztlon). N
49 2 0 .--'--d0 ---:::....d0 2HC1M.P.: 235-236" C. (decomposition).
50 2 0 -----d0 -.".:-...d0 M.P.:134 0., 21301 M.P.: 205 C.
Clix-CH2- N 51 2 0 ....d0 .:':'.':r'.....d0 M.P.:108-109 0., 2HC1 M.P.: 230 C. (decompo- CHz-CHr sltion).
EXAMPLE 52 A mixture of 9.6 g. of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (3-quinuclidin0ne hydrochloride), 7.5 g. of
furic acid in 200 ml. of toluene is heated under reflux with stirring in a flask with a Water trap attached for 16 hours. After cooling, the reaction mixture is concentrated under 2- y OXyis0butyric acid and 0.5 g. of concentrated sulreduced pressure, and then 50 ml. of water and 200 ml.
9 of chloroform are added to the residue. The mixture is made alkaline with sodium carbonate. The chloroform layer is separated, washed with water and dried over anhydrous magnesium carbonate, and the solvent (chloroform) is distilled off. The dark brown oily residue is colcrystallized from 2-propanol to give 6.5 g. of 8-allyl-3,3- diphenyl-Z-oxo 1,4 dioxa 8 azaspiro[4.5]decane hydrochloride as white crystals melting at 244 C. (decomposition).
Proceeding by the method of Examples 57 and 58, but
umn-chromatographed on 160 g. of neutralized, activated 5 substituting equivalent amounts of appropriate starting alumina and eluted with toluene. The eluate is concenmaterials, the following compounds are produced:
Example R n m X R R R Physical constant 59 CHEG-CHP 1 2 0 H Oxalate M.P.:159161 C.
trated to give 1-azazicyclo[2.2.2]octane-3-spiro-2-(5,5'- and the compounds identical to the products of above dimethyl-l',3-dioxolan-4'-one) as white crystals melting Examples 1, 2, 14-21, 23-26, 28-32, 34-37 and 40-51. at 82-85 C. ItS maleate melts at 14 C. EXAMPLES 53 to 56 To a mixture of 25 ml. of 37% formaldehyde and 25 Other examples of quinuclidine spiro compounds of the g. of 90% formic acid is added 10 g. of 3,3-diphenyl-2- formula oxo-1,4-dioxa-8-azaspiro[4.5]decane. The mixture is refluxed with stirring for 3 hours. After cOOling, the reaction mixture is made acid with 120 ml. of 4 N hydrochloric acid and concentrated under reduced pressure. The N 0-C=0 crystals obtained are recrystallized twice from ethanol to and acid addition salts thereof which can be produced give 5 of Y l P Y f a compound 111 3 and 4 combinedly represent azap1ro[4.5]decane hydrochloride as whlte crystals melting -CH CH m being 2 and n being 1) and a comat 0 pound (1V) in a manner Similar to that described in Proceeding by the method of Example 60, butsubst1 tut- Example 52 are as follows: mg equivalent amounts of appropriate starting materials,
the compounds identical to the product of above Exam- Example X R R Physical constant P165 34-37 are also produced- 53 o M.P.:154156 0., EXAMPLE 61 G $8 325 E I A mixture of 19 g. of 8-ethoXycarbonyl-3-meg11yl-2- o oxo-1-oxa-4-thia-8-azaspiro [4.5]decane and 200 of 54 S H H 213 214 35 20% solution of hydrogen bromide in acetic acid is 55 0 H G Lil-EJ547155 heated on a Water bath for 3 hours. After cooling, the acetic acid is distilled off under reduced pressure.1 Th(e1 a brown solid residue is crystallized from Z-propano an 56 s H CH3 8 lie lan iifiiioo, 40 recrystallized from methanol to give 10 g. of 3-methyl-2- fig}??? oxol-oxa-4-thia-8-azaspiro [4.5 decane hydrobromide as white crystals melting at 227 C. EXAMPLE 57 EXAMPLE 62 To a mixture of 105 of P Y -L A mixture of 20 g. of 8-ethoxycarbonyl-3,3-diphenyl-2- P hydrobromide and 10 of Sodium oxo-1,4-dioxa-8-azaspiro[4.5]decane, 35 g. of potassium carbonate in a mixed solvent of ml. of dimethylformh d id 300 1, f ethanol and 50 m1. of water is amide P 100 ml. of 31116116 is added of beIlZoyl heated on a Water bath for 22 hours. After cooling, the chloride The Whole mixture is fl d with stirring for solvent is distilled off and water is added to the residue. 10 hollfs- After Cooling, insoluble matter is filtered 01? The oil separated is extracted with chloroform. The chloand the filtrate is concentrated under reduced pressure. 50 rofo 1ayer i Washed i h water d dried over anhy. The residue is extracted with chloroform, the chloroform drous magnesium sulfate, and then the chloroform is layer is washed three times with water and dried over di ill d ff t give 11 g. of 3,3-diphenyl-2-oxo-1,4-dioxaanhydrous magnesium Sulfate, and then the chloroform 8-azaspiro[4.5]decane as white crystals melting at 113 is distilled off. The jelly like residue (pale brown) is dis- (3, solved in isopropyl ether and the solution is allowed to Proceeding by the method of Examples 61 and 62, by The Crystals Prficlpllaled are collected y filtration substituting equivalent amounts of appropriate starting and recrystallized from -l" P-' l0 g 7 of materials, the compounds identical to the products of Y 3,3 p l 0X0 Lf diOXa HZaSPiIO above Examples 5, 6, 8, 9 and 10 are also produced. [4.5]decane as white crystals melting at 127 C. EXAMPLE 63 MP 58 To a solution of 10 g. of 8-benzyl-3-methyl-2-oxo-1,4- dioxa-8-azaspiro[4.5]decane hydrochloride in 70 ml. of A mixtu of 10 of p Water are added 50 ml. of ethanol and 5 g. of 10% palp l z l hydrobromldei 10 P Sodlum ladium-carbon. Reduction is carried out with stirring unbonate and of allyl l?1'0m1de in a mlXed Solvent 9 65 der normal pressure at room temperature until the ab- 50 ml. of dlmethylformamide plus 100 ml. of toluene 1s sofption f hydrogen stops. After the reduction, the l. refluxed with stirring for 8 hours. After cooling, insoluble ladiumcarbon i filte d off, and the filtrat i concen. matter is filtered 01f and the filtrate is concentrated under trated under reduced pressure The white crystals obtained reduced pressure. The residue is extracted With ChlOI'O- are recrystallized twice from ethanol to give 45 g of 3- form. The chloroform layer is washed three times with methyl-Z-oxo-1,4-dioXa-8-aZaSpir0[4.5]decane hydrochlowater and dried over anhydrous magnesium sulfate, and id as hi crystals melting 229 then the chloroform is distilled 01f. The jelly-like residue is dissolved in a mixture of ethanol and isopropyl ether EXAMPLE 64 and ethanolic hydrochloric acid is added to the solution. To a solution of 10 g. of 8-benzyl-2-oxo-3-phenyl-1,4- The crystals formed are collected by filtration and redioxa-S-azaspiro[4.5]decane hydrochloride in 70 ml. of
water are added 100 ml. of 2-propanol and 6 g. of palladium-carbon. The resulting mixture is placed in an autoclave, the autoclave is charged with hydrogen at 80 atmospheres, and then the reduction is carried out at 60 C. for 1 hour. After cooling the palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. The white crystals obtained are washed with 2-propanol and recrystallized from ethanol to give 5 g. of 2-oxo 3 phenyl-1,4-dioxa-8-azaspiro[4.5]decane as white crystals melting at 194-195 C.
Proceeding by the method of Examples 63 and 64, but substituting equivalent amounts of appropriate starting materials, the compounds are identical to the products of above Examples 7 and 12.
EXAMPLE 65 To a solution of 8 g. of 8-methyl-3,3-diphenyl-2-oxo-1, 4-dioxa-8-azaspiro[4.5]decane (produced by Example 32) in a mixed solvent of 80 ml. of chloroform plus 30 ml. of methanol is added 5 g. of methyl iodide. The mixture is heated under reflux with stirring for 2.5 hours, and then further heated for 2.5 hours to complete the reaction. After cooling, the crystals obtained are collected by filtration and recrystallized from methanol to give 8 g. of 8,8 dimethyl-3,3-diphenyl-2-oxo-l,4-dioxa-8-azaspiro [4.5]decanium iodide as white crystals melting at 266- 267 C. (decomposition).
Other quaternary ammonium salts which can be produced from a compound (I) and alkyl halide or dimethyl sulfate by the method of Example 65 are as follows:
Melting point of quaternary salt (decom- Compound Quaternizing agent position) 32 Dimethyl sulfate 168 0. Methyl hydrogensulfate... 241 C. Ethyl bromide 249 C.
33 Methyl iodide 226 C.
52 Methyl iodide What is claimed is: 1. A compound selected from the group consisting of those spiro compounds encompassed by the following formula:
s (CHomJJH X-C(R1)(R2) wherein each of R and R is a member selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a p-chlorophenyl group and a benzyl group; wherein X is a member selected from the group consisting of an oxygen atom and a sulfur atom; wherein R represents a hydrogen atom; wherein R is a member selected from the group consisting of a hydrogen atom, an alkyl group of from 1 to 4 carbon atoms, a methoxy-carbonyl group, an ethoxy carbonyl group, an acetyl group, a benzoyl group, a benzyl group, a phenethyl group, a pyridylethyl group, a furfuryl group, a thenyl group, an allyl group and a propargyl group; and wherein m+n is an integer of 2 or 3, m being 0 or 1 and n being 2 or 3;
or a member selected from the group consisting of the pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof.
2. A compound according to claim 1, said compound being 8 methyl 3,3 diphenyl-Z-oxo-1,4-dioxa-8- azaspiro [4.5 decane.
3. A compound according to claim 1, said compound being 8 butyl 3,3 diphenyl 2 oxo 1,4-dioxa-8- azaspiro [4.5 decane.
4. A compound according to claim 1, said compound being 8 methyl 3 methyl 3-phenyl-2-oxo-1,4-dioxa-8- azaspiro [4.5 decane.
5. A compound according to claim 1, said compound being 8 methyl 3 benzyl-3-phenyl-2-oxo-1,4-dioxa-8- azaspiro [4.5 decane.
6. A compound according to claim 1, said compound being 8 (2 thenyl) 3,3-diphenyl-2-oxo-1,4-dioxa-8- azaspiro [4.5 decane.
7. A compound according to claim 1, said compound being 8 methyl 3,3 diphenyl 2-oxo-1-oxa-4-thia-8- azaspiro[4.5]decane.
8. A compound according to claim 1, said compound being 8 methyl 3,3 diphenyl 2-oxo-1,4-dioxa-8- azaspiro[4.5 1 decane methoiodide.
9. A compound according to claim 1, said compound being 8 methyl 3,3 diphenyl 2 oxo-l,4-dioxa-8- azaspiro [4.5 1 decane ethobromide.
10. A compound according to claim 1, said compound being 8 methyl 3,3 diphenyl 2 oxo-1,4-dioxa-8- azaspiro [4.5 decane methyl hydrogensulfate.
11. A compound according to claim 1, said compound being 8 methyl 3,3 diphenyl 2 oxo-1,4-dioxa-8- azaspiro[4.5]decane dimethyl sulfate.
References Cited UNITED STATES PATENTS HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner U.S. Cl. X.R.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16093771A | 1971-07-08 | 1971-07-08 |
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| US3784551A true US3784551A (en) | 1974-01-08 |
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|---|---|---|---|
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Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4940795A (en) * | 1987-10-05 | 1990-07-10 | Yamanouchi Pharmaceutical Co., Ltd. | Heterocyclic spiro compounds and methods for preparing the same |
| US5852029A (en) * | 1990-04-10 | 1998-12-22 | Israel Institute For Biological Research | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
| WO2006040329A1 (en) * | 2004-10-12 | 2006-04-20 | Novo Nordisk A/S | 1 ibeta- hydroxysteroid dehydrogenase type 1 active spiro compounds |
| US20090118259A1 (en) * | 2005-11-01 | 2009-05-07 | John Paul Kilburn | Pharmaceutical use of substituted amides |
| US20090124598A1 (en) * | 2005-11-01 | 2009-05-14 | Henrik Sune Andersen | Pharmaceutical use of substituted amides |
| US20090306048A1 (en) * | 2006-06-16 | 2009-12-10 | John Paul Kilburn | Pharmaceutical use of substituted piperidine carboxamides |
| US20090325932A1 (en) * | 2006-07-13 | 2009-12-31 | Soren Ebdrup | 4-piperidylbenzamides as 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors |
| US20100009968A1 (en) * | 2006-07-13 | 2010-01-14 | High Point Pharmaceuticals, Llc | 11beta-hydroxysteroid dehydrogenase type 1 active compounds |
| US20100056600A1 (en) * | 2007-03-28 | 2010-03-04 | Soren Ebdrup | 11beta-hsd1 active compounds |
| US20100076041A1 (en) * | 2007-03-09 | 2010-03-25 | John Paul Kilburn | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
| US20100087543A1 (en) * | 2007-04-24 | 2010-04-08 | Soren Ebdrup | Pharmaceutical use of substituted amides |
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- 1971-07-08 US US00160937A patent/US3784551A/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4940795A (en) * | 1987-10-05 | 1990-07-10 | Yamanouchi Pharmaceutical Co., Ltd. | Heterocyclic spiro compounds and methods for preparing the same |
| USRE34653E (en) * | 1987-10-05 | 1994-07-05 | Yamanouchi Pharmaceutical Co., Ltd. | Heterocyclic spiro compounds and methods for preparing the same |
| US5852029A (en) * | 1990-04-10 | 1998-12-22 | Israel Institute For Biological Research | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
| WO2006040329A1 (en) * | 2004-10-12 | 2006-04-20 | Novo Nordisk A/S | 1 ibeta- hydroxysteroid dehydrogenase type 1 active spiro compounds |
| US20090105289A1 (en) * | 2004-10-12 | 2009-04-23 | Novo Nordisk A/S | 11beta-hydroxysteroid dehydrogenase type 1 active spiro compounds |
| US8138342B2 (en) | 2004-10-12 | 2012-03-20 | High Point Pharmacueticals, LLC | 11β-hydroxysteroid dehydrogenase type 1 active spiro compounds |
| US20090118259A1 (en) * | 2005-11-01 | 2009-05-07 | John Paul Kilburn | Pharmaceutical use of substituted amides |
| US20090124598A1 (en) * | 2005-11-01 | 2009-05-14 | Henrik Sune Andersen | Pharmaceutical use of substituted amides |
| US8053431B2 (en) | 2005-11-01 | 2011-11-08 | High Point Pharmaceuticals, Llc | Pharmaceutical use of substituted amides |
| US20100168083A1 (en) * | 2006-03-21 | 2010-07-01 | Soren Ebdrup | Adamantane derivatives for the treatment of the metabolic syndrome |
| US8053447B2 (en) | 2006-04-07 | 2011-11-08 | High Point Pharmaceuticals, Llc | 11β-hydroxysteroid dehydrogenase type 1 active compounds |
| US20090306048A1 (en) * | 2006-06-16 | 2009-12-10 | John Paul Kilburn | Pharmaceutical use of substituted piperidine carboxamides |
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| US20110003856A1 (en) * | 2007-02-23 | 2011-01-06 | Soren Ebdrup | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
| US8334305B2 (en) | 2007-02-23 | 2012-12-18 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-β-hydroxysteroid dehydrogenase |
| US20100076041A1 (en) * | 2007-03-09 | 2010-03-25 | John Paul Kilburn | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
| US8153798B2 (en) | 2007-03-09 | 2012-04-10 | High Point Pharmaceuticals, Llc | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
| US20100056600A1 (en) * | 2007-03-28 | 2010-03-04 | Soren Ebdrup | 11beta-hsd1 active compounds |
| US20100137377A1 (en) * | 2007-04-11 | 2010-06-03 | Soren Ebdrup Et Al | Novel compounds |
| US20100087543A1 (en) * | 2007-04-24 | 2010-04-08 | Soren Ebdrup | Pharmaceutical use of substituted amides |
| US8383683B2 (en) | 2007-04-24 | 2013-02-26 | High Point Pharmaceuticals, Llc | Pharmaceutical use of substituted amides |
| WO2016079757A3 (en) * | 2014-11-19 | 2018-12-27 | Symed Labs Limited | Novel processes for preparing 5-hydroxymethyl-oxazolidin-2-one derivatives |
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